Conversion of nitrogen dioxide (no2) to nitric oxide (no)

ABSTRACT

Various systems, devices, NO 2  absorbents, NO 2  scavengers and NO 2  recuperator for generating nitric oxide are disclosed herein. According to one embodiment, an apparatus for converting nitrogen dioxide to nitric oxide can include a receptacle including an inlet, an outlet, a surface-active material coated with an aqueous solution of ascorbic acid and an absorbent wherein the inlet is configured to receive a gas flow and fluidly communicate the gas flow to the outlet through the surface-active material and the absorbent such that nitrogen dioxide in the gas flow is converted to nitric oxide.

CLAIM OF PRIORITY

This application claims the benefit of prior U.S. ProvisionalApplication No. 61/024,178, filed on Jan. 28, 2008, which isincorporated by reference in its entirety.

TECHNICAL FIELD

This description relates to controlled generation of nitric oxide.

BACKGROUND

Nitric oxide (NO), also known as nitrosyl radical, is a free radicalthat is an important signaling molecule in pulmonary vessels. Nitricoxide (NO) can moderate pulmonary hypertension caused by elevation ofthe pulmonary arterial pressure. Inhaling low concentrations of nitricoxide (NO), for example, in the range of 2-100 ppm can rapidly andsafely decrease pulmonary hypertension in a mammal by vasodilation ofpulmonary vessels.

Some disorders or physiological conditions can be mediated by inhalationof nitric oxide (NO). The use of low concentrations of inhaled nitricoxide (NO) can prevent, reverse, or limit the progression of disorderswhich can include, but are not limited to, acute pulmonaryvasoconstriction, traumatic injury, aspiration or inhalation injury, fatembolism in the lung, acidosis, inflammation of the lung, adultrespiratory distress syndrome, acute pulmonary edema, acute mountainsickness, post cardiac surgery acute pulmonary hypertension, persistentpulmonary hypertension of a newborn, perinatal aspiration syndrome,haline membrane disease, acute pulmonary thromboembolism,heparin-protamine reactions, sepsis, asthma and status asthmaticus orhypoxia. Nitric oxide (NO) can also be used to treat chronic pulmonaryhypertension, bronchopulmonary dysplasia, chronic pulmonarythromboembolism and idiopathic or primary pulmonary hypertension orchronic hypoxia. Typically, the NO gas is supplied in a bottled gaseousform diluted in nitrogen gas (N₂). Great care has to be taken to preventthe presence of even trace amounts of oxygen (O₂) in the tank of NO gasbecause the NO, in the presence of O₂, is oxidized to nitrogen dioxide(NO₂). Unlike NO, the part per million levels of NO₂ gas is highly toxicif inhaled and can form nitric and nitrous acid in the lungs.

SUMMARY

In one aspect, an apparatus for converting nitrogen dioxide to nitricoxide includes a receptacle including an inlet, an outlet, asurface-active material coated with an aqueous solution of ascorbic acidand an absorbent, wherein the inlet is configured to receive a gas flowand fluidly communicate the gas flow to the outlet through thesurface-active material and the absorbent such that nitrogen dioxide inthe gas flow is converted to nitric oxide. The absorbent can be silicagel or activated alumina.

In another aspect, a method of providing a therapeutic amount of nitricoxide to a mammal includes diffusing nitrogen dioxide into a gas flow,exposing the nitrogen dioxide to a surface-active material coated withascorbic acid and an absorbent to eliminate the by-products of ascorbicacid oxidation and transporting the nitric oxide in a therapeutic amountto a mammal.

In a further aspect, a system of delivering a therapeutic amount ofnitric oxide to a mammal includes a gas source of nitric oxide; and aNO₂ scavenger selected from the group consisting of proline anddiphenylamine.

In one aspect, a recuperator for converting nitrogen dioxide into nitricoxide includes an exit shell including an outlet, an inside shellwherein the inside shell includes perforated inner and outer tubes withfixed annulus, a surface-active material coated with an aqueous solutionof ascorbic acid, an absorbent and a top cap including an inlet whereinthe inlet is configured to receive a gas flow and fluidly communicatethe gas flow to the outlet through the surface-active material such thatnitrogen dioxide in the gas flow is converted to nitric oxide. Therecuperator further includes an annular ring around the top cap.

In another aspect, a system for delivering nitric oxide to a patient,includes a gas source of nitrogen dioxide, dinitrogen tetraoxide, ornitric oxide, a first device having an inlet, an outlet, and a poroussolid matrix positioned between the inlet and the outlet, wherein theporous solid matrix is coated with an aqueous solution of anantioxidant, and wherein the inlet is configured to receive a gas flowfrom the source and fluidly communicate the gas flow to the outletthrough the porous solid matrix to convert nitrogen dioxide in the gasflow into nitric oxide, and a recuperator coupled to the outlet of thefirst device, the recuperator converting nitrogen dioxide into nitricoxide prior to delivery to the patient. The recuperator can have a flowresistance of less than 3 cm of water pressure at a flow of 60 L/minute.The recuperator can have a flow resistance of less than 1 cm water at 15L/min. The recuperator can operate at atmospheric pressure. Therecuperator can have an oxygen concentration of in the range of 21 to100%. The recuperator can have a humidity of dry to 99% (noncondensing). The recuperator can be thermally insulated. The recuperatorcan be coupled to the outlet of a first device through a humidifiedline. The humidified line can be heated. The humidified line can beheated to about 35° C. The recuperator can be coupled to a NO/NO₂ gasanalyzer. The recuperator can further include a particle filter.

In a further aspect, a method of sampling NO and NO₂ gas in a NOdelivery system includes obtaining a sample of gas, diluting the sampleof gas with air, and measuring the amount of NO and NO₂ gas with a gasanalyzer. The sample of gas can be diluted by 50%. The sample of gas canbe diluted by 33%. The sample of gas can be diluted with air from thehospital room. The sample of gas can be diluted with air from the wall.The sample of gas can be diluted with oxygen.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF DRAWING

FIG. 1 is a block diagram of a cartridge that converts NO₂ to NO.

FIGS. 2A-B are diagrams depicting implementations of a disc filterrecuperator.

FIGS. 3A-B are diagrams depicting implementations of a tubular filterrecuperator.

FIG. 4 is a diagram depicting an implementation of a recuperator.

FIG. 5 is a diagram depicting another implementation of a recuperator.

FIGS. 6A and B are flow diagrams depicting Nitric Oxide (NO) deliverysystems and flow of the gasses.

FIG. 7 is a graph depicting the variation of pressure drop with size ofa disc recuperator.

FIG. 8 is a flow diagram depicting nitric oxide delivery for anintensive care unit.

FIGS. 9A-D are diagrams depicting geometrical depictions of dish filtersand tube filters.

DETAILED DESCRIPTION

Nitric Oxide (NO) is very well known and well-studied gas. NO isnormally present in the atmosphere (as a pollutant from automobiles andpower plants) at concentrations between 0.010 and 0.500 parts permillion (ppm), and NO concentrations may reach 1.5 ppm in heavy traffic.NO is also present in tobacco smoke at levels as high as 500 ppm to 2000ppm.

For medical applications, NO gas, like oxygen has been studied and usedto treat patients for many years. In biological systems, NO is amolecule that is naturally produced in the human body. NO is one of thefew gaseous signaling molecules known. NO is a key vertebrate biologicalmessenger, playing a role in a variety of biological processes. NO ishighly reactive (having a lifetime of a few seconds), yet diffusesfreely across membranes. These attributes make NO ideal for a transientsignal molecule between adjacent cells and within cells. Severalpharmaceutical products, such as Nitroglycerin, amyl nitrite andSildenafil (Viagra) serve as vasodilators because they either release orcause NO to be released in the body. In 1987, the biologic similaritiesof NO to endothelium-derived relaxing factor were demonstrated.Subsequently, NO and endothelium-derived relaxing factor were consideredthe same entity. During the late 1980s and early 1990s, inhaled NOemerged as a potential therapy for the acute respiratory distresssyndrome (ARDS), sickle cell anemia, COPD and other conditions. Sincethen NO has been shown to reduce persistent pulmonary hypertension andalso to reduce pulmonary hypertension without any undesired drop insystemic blood pressure, which is valuable when treating heart and lungtransplant patients and other patients having undergone interventionalcardiovascular procedures. The gas was readily available for many yearsfrom several suppliers as were several competing CE marked deliverysystems. During the 1990s the medical use of the gas was patented andthe cost has increased substantially. Even with this restriction, NO iscurrently routinely and safely used under institutional or countywideprotocols for many uses outside of the approved indications forneonates.

When delivering NO for therapeutic use to a mammal, it can be importantto avoid delivery of nitrogen dioxide NO₂ to the mammal. NO₂ can beformed by the oxidation of NO with oxygen (O₂). The rate of formation ofNO₂ is proportional to the O₂ concentration multiplied by the square ofthe NO concentration—that is, (O₂) (NO)*(NO)═NO₂.

In one aspect, a NO delivery system that converts NO₂ to NO is provided.The system employs a surface-active material coated with an aqueoussolution of antioxidant as a simple and effective mechanism for makingthe conversion. One example of a surface-active material is silica gel.Another example of a surface-active material that could be used iscotton. The surface-active material may be or may include a substratecapable of retaining water. Another type of surface-active material thathas a large surface area that is capable of absorbing moisture also maybe used. More particularly, NO₂ can be converted to NO by passing thedilute gaseous NO₂ over a surface-active material coated with an aqueoussolution of antioxidant. When the aqueous antioxidant is ascorbic acid(that is, vitamin C), the reaction is quantitative at ambienttemperatures.

The oxidation of ascorbic acid with oxygen under moist conditions can becomplex, with over 50 different compounds having been reported. (See J.C. Deutsch, “Spontaneous hydrolysis and dehydration of dehydroa,”Analytical Biochemistry, Vol. 260, no. 2, pages 223-229 (Jul. 1, 1998);Dong Bum Shin and Milton S. Feather, “3-deoxy-L-glycero-pentos-2-ulose(3-deoxy-L-xylosone) and L-threo-pentos-2-ulose (L-xylosone) asintermediates in the degradation of L-ascorbic acid,” CarbohydrateResearch, Vol. 280, pages 246-250 (Dec. 15, 1990); Eiji Kimoto et al.,“Analysis of the transformation products of dehydro-L-ascorbic acid byion-pairing high-performance liquid chromatography,” AnalyticalBiochemistry, Vol. 214, pages 38-44 (1993), Academic Press; Steven R.Tannenbaum et al., “Inhibition of nitrosamine formation by ascorbicacid,” The American Journal of Clinical Nutrition, Vol. 53 (1 Suppl.)pages 247S-250S (January 1990), all of which are incorporated byreference in their entireties). The reaction generally leads todehydroxy ascorbic acid, which can then be further degraded intomultiple species.

FIG. 1 illustrates an example of a cartridge 100 for generating NO byconverting NO₂ to NO. The cartridge 100, which may be referred to as aNO generation cartridge, a cartridge, or a cylinder, includes an inlet105 and an outlet 110. Screen and glass wool 115 are located at both theinlet 105 and the outlet 110, and the remainder of the cartridge 100 isfilled with a surface-active material 120 that is soaked with asaturated solution of antioxidant in water to coat the surface-activematerial. The surface-active material can be silica gel. The screen andglass wool 115 also is soaked with the saturated solution of antioxidantin water before being inserted into the cartridge 100. In the example ofFIG. 1, the antioxidant can include ascorbic acid. In other embodiments,the antioxidant can include alpha tocopherol or gamma tocopherol.

The moist silica gel of the cartridge can adsorb and bind up the vastmajority of the products of the side reactions.

In the presence of moisture, oxygen and NO, NO₂ forms N₂O₃, N₂O₄ and thenitrite ion. In one embodiment, these reactants can combine with an NO₂scavenger which can include the common amino acid, proline, to formN-nitroso proline. N-nitrosproline is non carcinogenic. This reactionhas been used in vivo by Tannenbaum The American Journal of ClinicalNutrition, Vol. 53 (1 Suppl.) pages 247S-250S (January 1990), andOhshima and Bartsch (Cancer Res. Vol. 41, p. 3658-3662 (1981), tomeasure the nitrosation capacity of the body, and to show that theaddition of Vitamin C can reduce this capacity. Such a reaction can beused to trap out NO₂ in the gas phase from an air stream containingmoist NO₂ in the presence of oxygen and NO. The proline can be in theform of a crystalline powder. Proline can be placed in a tube and gascan be allowed to flow over it. The NO₂ that is present can bindirreversibly with the proline to form N-nitroso proline. The applicationof this reaction is to use this reaction as a scavenger to remove thelast minute traces of NO₂ from an air stream containing NO and oxygenand air. In one embodiment, such a NO₂ scavenger can be used in a NOdelivery system to allow any NO₂ that is present to bind irreversiblywith the proline to form N-nitroso proline.

The proline can be in the form of a powder, or as a solution that hasbeen deposited onto a substrate such as silica gel, activated aluminaand charcoal. Other appropriate substrates can be used as long asproline is available to react with NO₂ gas. In one embodiment, anaqueous solution of proline in water can be used. In another embodiment,diphenylamine or any secondary or tertiary amine can be used to reactwith NO₂ gas. Examples of secondary amines can include dimethylamine,methylethanolamine or 2-(methylamino)ethanol, cyclic amines such asaziridine, azetidine, pyrrolidine and piperidine. Examples of tertiaryamine can include trimethylamine, dimethylethanolamine (DMEA),2-(dimethylamino)ethanol or bis-tris.

Preferably, any material can be used where the Nitroso product will notbe carcinogenic or toxic. In other embodiments, any compounds that bindwith the NO₂ to form organic compounds can be used. Products include butare not limited to: nitro, nitroso, or azo as long as the NO₂ ischemically bound up so as to remove it from the system.

In one embodiment, an NO₂ scavenger can be included in a NO deliverysystem. The purpose of the NO₂ scavenger is to remove any NO₂ gas thatmay have been formed in the ventilator and during storage in a gas bagor other temporary gas storage device. In another embodiment, the NO₂scavenger can remove NO₂ that is formed in the gas plumbing lines fromthe exit of the NO generation cartridge. The NO₂ scavenger can serve asa safety device to reduce the NO₂ levels to below 0.1 ppm, at any flowand at any NO concentration, prior to delivery to a patient.

In another aspect, a recuperator is included in the NO delivery system.The purpose of the recuperator is to convert any NO₂ gas that may havebeen formed in the ventilator and during storage in a gas bag or othertemporary gas storage device to NO. In one embodiment, the recuperatoris a device that is immediately adjacent to the patient. It serves thesame purpose as the main NO generation cartridge, namely to convert NO₂to NO. In another embodiment, the recuperator coverts NO₂ that is formedin the gas plumbing lines from the exit of the cylinder NO generationcartridge to NO. The recuperator can be a cartridge that is needed torecover any NO₂ that was formed in the ventilator and in the gas linesfrom the reaction of NO and Oxygen. The recuperator can serve as asafety device to reduce the NO₂ levels to below 0.1 ppm, at any flow andat any NO concentration, prior to delivery to a patient.

In one embodiment, the flow resistance for the recuperator can be as lowas possible, for example, less than 3 cm of water pressure at a flow of60 L/minute, and/or <1 cm water at 15 L/min. The recuperator can operateat atmospheric pressure. The oxygen concentration at the recuperator canbe in the range of 21% to 100%. The humidity at the recuperator can be0% to 99%. The recuperator can be thermally insulated to prevent watercondensation. The inlet to the recuperator can be from the humidified(and heated) line that is delivering gas to the patient. This line canbe typically heated to about 35° C. to prevent water condensation in thelines.

The exit side of the recuperator can be a sample probe that goes to theNO/NO₂ gas analyzer. The sample line can be diluted with an equal volumeof air so as to reduce the relative humidity and to minimize the rate offormation of NO₂ from Oxygen in the sample line to the analyzer. Theweight of the recuperator can be kept as low as possible, so that it isnot unwieldy, under 2 pounds but preferably under 1 pound or under 0.5pounds. The exit from the recuperator can go directly to the patient bymeans of a short (approximately 6 inch) length of roughly 1 inchdiameter ventilator tubing. The recuperator can be disposable and can befor a single use only. The recuperator can incorporate a particle filterto prevent any possibility that trace amounts of dust from therecuperator being delivered to a patient, for example, fine silica gelor ascorbic acid for the recuperator, or fine proline for the scavenger.The same filter material will also prevent bacteria and other particlesfrom being delivered to the patient.

In one embodiment, the recuperator is provided as a disc as exemplifiedin FIGS. 2A and B. In a further embodiment, the recuperator can includea common filter design that is widely used in industry which is atubular design with co-axial tubes. This type of design is especiallycommon in water filters and for use in compressed in air lines. Inanother embodiment, the recuperator is provided as a tubular filter asexemplified in FIGS. 3A and B. As depicted in FIGS. 3A and B, thetubular filter can be constructed from three concentric tubes, with thefilter medium being held tightly in place in a perforated section of theinterior. The tubular filter can hold the silica gel or ascorbic aciddust in place in the annulus between the two perforated tubes. A filtermedium can be placed on both contact sides of the silica gel or ascorbicacid dust. The powder or dust can be compressed during filing withoutthe compression material coming into contact with the flowing airstream. The aspect ratio will be easier to handle adjacent to thepatient, where a small diameter shape can be used. The tubular filtercan include an exit shell as depicted in FIG. 3B, an inside shell thatincludes perforated inner and outer tubes with fixed annulus and anannulus filled with silica gel or ascorbic acid dust. The inner andouter annulus can be lined with filter material. In one embodiment, thefinal assembly of the tubular filter is depicted in FIG. 3B. The finalassembly can include a top cap and an annular ring at the top can keeppressure on the silica gel or ascorbic acid dust.

In one embodiment, a method of NO and NO₂ gas sampling is provided. Forexample, for 100 ppm of NO and 100% oxygen, 1.70 ppm of NO₂ can beformed in the gas sampling lines from the reaction of NO with oxygen.The problem is how to sample for NO₂ in a gas stream that has thereaction of NO and oxygen going on at the same time. This is made worseat high NO concentrations. For example at 200 ppm NO the rate offormation of NO₂ in the sample line is 4 times the rate as compared to100 ppm. Also at 100% oxygen the rate is 5 times the rate in air. To getan accurate reading of what was in the line at the patient there is aneed to either sample quickly, or slow the reaction down somehow. Bydiluting by 50%, the rate is decreased 4 fold due to the drop in NOconcentration and approximately 2.5 fold by the drop in Oxygenconcentration.

In one embodiment, the sample tube from the patient to the detector canbe diluted up to 66%, or up to 50% or up to 33%. The sample can bediluted at the sample point. The sample can be diluted with air. Forexample, dilution of one part sample and one part with air can reducethe water concentration in the sample. In another embodiment, the samplecan also be diluted as follows: one part sample and two parts with airfrom the room (e.g. hospital room). Alternatively, the sample can alsobe diluted using bone dry air from the wall.

In a further embodiment, the sample tube can be spliced in two or three,adjacent to the sampling point on the recuperator. This can be done for50 or 66% dilution.

EXAMPLES Gas Cylinder Cartridge Design

In another aspect, the gas cylinder and appropriate amount of NO₂ forclinical use is provided. The FDA standard room size: 3.1×6.2×4.65m=89.3 m³=89,300 L. The OSHA NO₂ level is 5 ppm. All the three gascylinders described herein are approximately equivalent in the amount ofgas that they can deliver.

Size AS of the cylinder is pressurized to 2000 psi. The sudden releaseof the entire contents of 3600 L of 124 ppm would lead to a NO₂ level of5.0 ppm in the room, if there was no air exchange. Thus, in order tomeet the current FDA requirement for safety, the highest concentrationin a gas cylinder of this size and type should be 100 ppm of NO₂ (with abuilt in safety factor). The cylinder that is used in the lab willdeliver 3,600 liters of gas (without dilution) containing 100 ppm ofNO₂. At 5 L/min, this gas cylinder will last for 720 minutes=12 hours.At 48 pounds, without the regulator and top, this cylinder is far tooheavy to be picked up by a nurse or therapist, and has to be moved on awheeled cart.

Size AQ/BL188 2000 psi cylinder is currently in use in hospitals. Thesudden release of the entire contents of 1918 L of 233 ppm would lead toa NO₂ level in the hypothetical room of 5.0 ppm. Thus, in order to meetthe current FDA requirement for safety, the highest concentration in agas cylinder of this size and type should be 200 ppm of NO₂ (with abuilt in safety factor). For a cylinder of this size and 200 ppm of NO₂,the ideal oxygen level would be 70-74%. This pressure cylinder willdeliver 3836 liters of gas (after dilution) containing 100 ppm of NO₂.At 5 L/min, this gas cylinder will last 767 minutes=12.8 hours. Thiscylinder weighs 30 pounds and is still too heavy to be picked up by anurse. It is a bit more maneuverable but still needs a wheeled cart fortransport.

Luxfer's ME36 3000 psi cylinder holds 992 Liters at a pressure of 3000psi instead of 2000 psi. The sudden release of the entire contents of992 L of 450 ppm would lead to a NO₂ level of 5.0 ppm in thehypothetical room. Thus, in order to meet the current FDA requirementfor safety, the highest concentration in a gas cylinder of this size andtype should be 400 ppm of NO₂ (with a built in safety factor). Thiscylinder however, weighs only 8.3 pounds compared to INO's 30 pounds.The contents of this small, high pressure cylinder would last as long asthe AQ and the AS. This translates into the cylinders being used up attwice or four times the rate of INO but at less than ⅓^(rd) of theweight this is a reasonable trade off. The key advantage is that thecylinder is small and light enough to be stocked in a pharmacy andpicked up by a nurse with one hand. The ideal oxygen level in a cylinderof this size would be about 60%. The Luxfer high pressure miniature gascylinder will deliver 3968 liters of gas (with dilution) containing 100ppm of NO₂. At 5 L/min, this gas cylinder will last 793 minutes=13.2hours. At only 8.3 pounds, this cylinder can be picked up by a nursewith one hand. It is small enough to be stored in a hospital pharmacy.The 3000 PSI Luxfer Cylinder offers the best performance and is thepreferred package. Table 1 shows the specifications of the cylindersdescribed herein.

The physical layout of the recuperator is able to accommodate the 4.5inch diameter cylinder, and an output tube that contains activatedcharcoal powder. As an example, a tube design is exemplified in FIG. 4.

The revised design depicted in FIG. 5 has the two main tubes as closetogether as possible, with the small vertical tubes tucked in close. Theentire package has to fit inside a 4.5 inch or less gas cylinder top.This is shown schematically in FIG. 5. Each main tube that holds theascorbic acid/silica gel dust has an inside diameter of about 1 inch.The inlet and outlet tubes need to be on the same side. The short tubecan contain a small amount of activated charcoal to remove traces ofacetaldehyde. Several embodiments of the entire package for use in anIntensive Care Unit are depicted in FIGS. 6A and B.

The gas bottle contains a mixture of 60% oxygen with the balance beingN₂. The gas also contains about 400 ppm of NO₂. This gas leaves the gascylinder through a built in regulator where the pressure is reduced tothe 20 to 100 psi level. The gas is attached to a separate blending boxby means of a unique quick disconnect.

The gas containing 400 ppm NO₂ is then blended with an air/oxygenmixture to reduce the NO₂ concentration to the therapeuticconcentration. In current use, this is 0.1 to 80 ppm. In one aspect ofthe system, this could be extended upwards to >200 ppm. The blender dialis calibrated in ppm equivalents of NO. The gas leaving the blenderflows onto the NO generation cartridge by means of a quick disconnectattachment. The air oxygen blender is a conventional design and isavailable commercially. The air and oxygen are typically supplied fromthe hospital wall supply as a utility. Alternatively, the gas can flowthrough the ventilator first before the cartridge to reduce the gaspressure from 50 to 20 psa.

The cartridge converts the NO₂ to NO. As the gas leaves the cartridge,the gas now has NO at the proper therapeutic concentration in an airoxygen blend of the appropriate oxygen concentration. The gas leavingthe cartridge is connected back to the blending box by means of a quickdisconnect fitting, where the oxygen concentration can be sampled anddisplayed. In one embodiment, an oxygen sensor can be used to preciselyset the appropriate oxygen concentration.

The reason for the three connections to the blender box is to allowquick replacement of the gas cylinder. A second cylinder will be plumbedto an identical set of three quick disconnect fittings on the blenderbox. When a cylinder needs to be changed, a single three stack valve isused to switch from one gas cylinder to another, allowing for the emptycylinder to be replaced. This is not shown on the FIG. 6A.

The gas mixture from the blender box becomes replaces the oxygen feed ona conventional medical ventilator. The ventilator is then used in itsconventional mode and can perform whatever ventilatory cycles that thetherapist desires for a particular patient. The device is intended toprovide the physician a mechanism for delivering a low concentration(dose) of pure NO gas in a mixture of oxygen and air. The gas passesthrough a mechanical or manual ventilator and travels throughrespiratory tubing and a mask or tube to the patient's lungs. The gasflow can be regulated by a mechanical ventilator or manual ventilationor by delivery directly to the patient from the pressurized gas tank(for spontaneously breathing patients). The device allows the physicianto independently adjust the NO concentration and the oxygenconcentration of the delivered gas.

Indication for Use

The device is indicated to provide pure NO gas at differentconcentrations in an oxygen/air mixture.

General Product Description

In one embodiment, The Nitric Oxide (NO) Generator and Delivery Systeminclude five components that work together to create, deliver andmonitor pure Nitric Oxide (NO) gas in an oxygen/air mixture. The gastravels through standard anesthesia and respiratory breathing devicesfor inhalation by the patient. The anesthesia part is only needed toprovide variable flow rates and/or to assist patients who are notbreathing on their own. In its simplest form the gas bottle stands aloneand the gas is converted to NO as it leaves the gas bottle. With thisapproach the gas is then fed into a mask or a cannula. The gas flow isprovided by mechanical or manual ventilation or by the pressurization ofthe tank (for spontaneously breathing patients). The concentration of NOand Oxygen are determined and adjusted by the physician based on eachpatient's condition and needs.

Product Components

Gas Tanks

The first component is a pressurized aluminum gas tank with a smallquantity of Nitrogen Dioxide (NO₂) gas in an Oxygen/Air mixture. Thismixture cannot be inhaled without processing by the other components asit would be toxic. The tanks will come with a standard regulator tolimit the pressure of the gas to the mixer. Tanks will have concentratedlevel of NO₂ gas and in a fixed Oxygen/Air ratio. These concentrationswill be adjusted using the mixing system below. Tanks used or transportwill be at set concentrations of NO₂ gas and Oxygen/Air and will notrequire mixing.

Mixing System

The mixing system includes two standard gas blenders that are connectedand an oxygen sensor. The first mixing chamber takes medical oxygen andair, which can be provided from pressurized tanks or the hospital's gassystem. A knob allows selection of the desired FiO₂ (fraction ofinspired oxygen) of the gas to be delivered to the patient which adjuststhe oxygen/air mixture in the mixing chamber as measured by the oxygensensor. The output of this mixture is fed into a second mixing chamberwhere it is mixed with the NO₂ gas from the gas tank described above.The knob to this mixing chamber allows the physician to select theconcentration of NO gas to be delivered to the patient. The output ofthis mixing chamber is the passed though the gas converter andpurification cartridge described below. This allows variable NO andoxygen concentration levels which are independent of each other.

Gas Converter and Purification Cartridge

The gas mixture from the last mixer will flow through the Gas Converterand Purification cartridge. This cartridge will convert all NO₂ gas intoNO gas and remove any impurities in the entire gas mixture. Theconcentration of NO gas will be the same as the concentration of the NO₂gas as the conversion is essentially 100%. The concentration of theoxygen (oxygen/air ratio) will not be changed. The output of thecartridge will be delivered to the mechanical or manual ventilationsystem and appropriate pressures. Tanks used for transport will also befitted with a flow meter to regulate the flow of the gas to the patient.

Recuperator Cartridge

The Recuperator cartridge will be placed at the patient end of theinspiratory limb of the patient's breathing tubing. This cartridge willcontain the same technology as the Gas Converter The purpose of thiscartridge is twofold. First, it will reconvert any NO₂ gas back into NOthat may have formed through the reaction of the NO gas with oxygen.Second it provides bacterial and viral filtration of the delivered gas.

Disc Recuperator

The obvious format for the recuperator is to make it much like the gascylinder device, but with the diameter of the order of 3 to 4 inches,and the cartridge depth reduced from 5.5 inches to less than 0.3 inches.A cartridge like this has a pancake shape and would look similar to theparticle filters that are used with some respiratory equipment.

The equations below show how the pressure drop across the cartridge willvary as a function of radius and the depth. For a constant volumecartridge, the pressure drop varies with the fourth power of the radius.

V₁ = π r₁²l₁ l₁ = V₁/π r₁²$p \propto {l_{1}\text{/}\pi \; r_{1}^{2}} \propto \frac{V_{1}}{\pi \; r_{1}^{2} \times \pi \; r_{1}^{2}} \propto \frac{V}{\pi^{2}r_{1}^{4}}$$\frac{p_{2}}{p_{1}} = {\frac{\pi \times \pi \; V_{2}}{V_{1} \times \pi \times \pi}\frac{r_{1}^{2} \times r_{1}^{2}}{r_{2}^{2} \times r_{3}^{2}}}$

For constant volume of material

${p_{2}/p_{1}} = ( \frac{r_{1}}{r_{2}} )^{4}$

If volume material is half, then

${p_{2}/p_{1}} = {0.5( \frac{r_{1}}{r_{2}} )^{4}}$

The gas bottle cartridge, which has a radius of 0.4 inches and a depthof 5.5 inches, has a pressure drop that was measured experimentally of2.7 psi=187 cm H₂O water. The calculations of pressure drop for variousdiameters are shown in Table 2. A pressure drop of 0.2-0.3 cm water at 5L/min is needed to attain the design goal of 3.0 cm H₂O at 60 L/min. Inorder to achieve this low a pressure drop, the diameter of the flat discwould need to be 4.0 to 4.5 inches. If it were to have the same amountof material as the current cylinder cartridge, the depth would need tobe 0.56 cm at 4.00 inches and 0.44 inches at 4.5 inches.

A flat disc of 3 inches diameter and a 1.0 cm thickness, has been testedin the laboratory and has been shown to perform as well as the cylindercartridge. The variation of pressure drop with size, where all thefilters have the same volume of material, is shown in FIG. 7. Variousconcepts have been evaluated on how to build such a device. Thedifficulty is how to encapsulate the silica gel or ascorbic acid dustbetween two very thin filter cloths, and have not only uniform thicknesseverywhere, but also no settling of the silica gel or ascorbic aciddust. Settling would be catastrophic and could lead to channeling andfailure. An example of one such design is shown in FIG. 2B.

A comparison of the pressure drop across the disc and tubular filtersare shown mathematically below and in FIGS. 9A and B.

Dish Filter Tube Filter A = πr² A = 2πr · l V = πr²t V = 2πr · l · t$t = \frac{V}{2\pi \; {rl}}$

For Cylinder:

${p \propto \frac{t}{A}} = {\frac{t}{2\pi \; {rl}} = {\frac{V}{( {2\pi \; {rl}} )^{2}} = \frac{V}{4\pi^{2}r^{2}l^{2}}}}$

For Dish:

$p \propto \frac{V}{\pi^{2}r^{2}r^{2}}$

Essentially, the analysis shows that the pressure drop of the tubularfilter, like the disc filter, is proportional to the surface area (theinner circumference of the tubular filter) and the thickness of the bed.The detailed calculation of size and pressure drop are shown next and inFIGS. 9C and D.

Tube Calculation Continued

Volume of outer tube:

V ₂ =πr ₂₁ ² l

Volume of inner tube:

     V₁ = π r₁²l $\mspace{79mu} \begin{matrix}{V = {{Volume}\mspace{14mu} {of}\mspace{14mu} {silica}\mspace{14mu} {gel}\mspace{14mu} {or}\mspace{14mu} {ascorbic}\mspace{14mu} {acid}\mspace{14mu} {Dust}}} \\{= {V_{2} - V_{1}}} \\{= {{\pi \; r_{2}^{2}l} - {\pi \; r_{1}^{2}l}}}\end{matrix}$ $\begin{matrix}{\mspace{79mu} {r_{2} = \sqrt{\frac{Volume}{\pi \; l} + \frac{\pi \; r_{1}^{2}l}{\pi \; l}}}} \\{= \sqrt{\frac{Volume}{\pi l} + r_{1}^{2}}}\end{matrix}$For  Volume = 2.76  cubic  inches  (5.5  inches − 0.8  inches  cylinder)     r₁ = 0.5  inch      1 = 3.0  inches$\mspace{79mu} {r_{2} = {\sqrt{\frac{2.76}{\pi \times 3} + (0.5)^{2}} = {\sqrt{0.29 + 0.25} = {\sqrt{0.54} = 0.73}}}}$     gap = 0.23inches ≡ 0.58cm $\begin{matrix}{\mspace{79mu} {{Area} = {2\pi \; {rl}}}} \\{= {2{\pi (0.5)}(3)}} \\{= {94{{sq}.{inches}}}}\end{matrix}$      Equivalent  area  to  disc  3.5⁴ perimeter     Pressure  drop = 0.5cm  H₂O

These equations were then used to evaluate a variety of shaped tubularfilters and compared to the disc filter. For example, a 4 inch longtubular filter with an internal radius of 0.5 inch (1 inch id) and anouter annulus diameter of diameter of 1.25 inches would have an outershell diameter of about 1.75 inches. A tubular filter with this aspectration would have a pressure drop at 5 l/min of only 0.19 cm H₂O, whichis equivalent to a 4.5 inch diameter disc. The gap between the tubes,called the annulus, would have a spacing of 0.4 cm. See Table 3 FromTable 3, assume that the performance of a disc that is 5 inches indiameter is wanted, which would have an effective surface area of 19.63sq inches and a pressure drop of 0.12 cm of water. In a tubular version,the same surface area and pressure drop can be achieved with a insidediameter of 0.57 inches and an od of 0.70 inches, provided that the tubewas 5.50 inches in length.

Gas Monitoring

The system may require gas sensors to monitor and display theconcentration of NO and NO₂ that is delivered to the patient. These canbe commercially available monitors and should be equipped with alarmcapability. A figurative representation of the system is shown on FIG.8.

For 100 ppm of NO and 100% oxygen, it is shown by both experiment andcalculation that 1.70 ppm of NO₂ is formed by the time the sample passesthrough about 2 meters of tubing, thru a large volume water drop outfilter and into the PrinterNox, which is a commercial electrochemicalgas analyzer for measuring NO and NO₂ for inhalation applications. Thesample can also be >100 saturated with water and the water drop outfilter is essential. This is a typical problem that is encountered instack monitoring from incinerator and power plant smoke stacks. Thereare several possible solutions:

First, heat the sample lines to keep the water in the vapor phase. Ifthe instrument also runs hot, then the water filter can be eliminatedand the sampling time reduced, thereby reducing the NO₂ formation. It isnot a good approach for NO₂ sampling since the rate of formation islinear with time and square power with NO₂.

Second, sample at the source. This does work, but the condensing waterissue remains.

Third, dilute the sample. This does three critical things:

-   -   1. It dilutes the sample which reduces the formation of NO₂ from        NO and O₂. This makes sampling down lines possible otherwise        most of the NO that is measured at the analyzer will be formed        in the sampling lines.    -   2. It decreases the humidity, which prevents condensation of        water in the lines and thereby eliminates the need for a water        drop out filter.    -   3. It reduces the NO level by 50% which brings the machine into        the working range of the PrinterNOx detection cells

Consider a Sample Tube with Dilution of One (50%).

-   -   Initial conditions: 100 ppm NO, 100% oxygen and condensing water        (>100%)    -   With 50% dilution: 50 ppm NO, 60.5% oxygen, and greatly reduced        humidity.    -   At detector: Rate of formation of NO₂ reduced by 4*100/60.5=6.6        NO₂ reduced from 1.70 to 0.26 ppm

With removal of the large volume water condensation filter volume, thelevel will come down even further.

NO readings are reduced at all concentrations by 50%. This means 20 ppmreads as 10, and 2 ppm reads as 1 ppm. This is corrected for bycalibration, but the precision will be reduced by 50%.

NO₂ formation in the lines is effectively reduced to zero at normalconcentrations. For example, even at 80 ppm NO, the NO₂ formed in thelines would be 1.09 ppm without dilution and <0.16 ppm with dilution.

Consider a Sample Tube with Dilution of Two (33%).

-   -   Initial conditions: 100 ppm NO, 100% oxygen and condensing water        (>100%)    -   With 33% dilution: 33 ppm NO, 47% oxygen, and greatly reduced        humidity.    -   At detector: Rate of formation of NO₂ reduced by 9*100/47=20 NO₂        reduced from 1.70 to 0.09 ppm

NO readings are reduced at all concentrations by ⅓rd. This means 20 ppmreads as 6.67, and 2 ppm reads as 0.67 ppm. This is corrected for bycalibration, but the precision will be reduced by ⅓^(rd).

NO₂ formation in the lines is effectively reduced to zero at normalconcentrations. For example, even at 80 ppm NO, the NO₂ formed in thelines would be 1.09 ppm without dilution and <0.05 ppm with dilution.

Humidity

At 37° C., body temperature, the amount of water at 100% relativehumidity is 44 g/M³. The air in a hospital is typically at 50% relativehumidity and a temperature of 22° C. Air at this temperature contains 10g/M³.

Diluting one part sample and one part with air from the hospital roomwould reduce the water concentration in the tube down to 27 g/M³. Thisamount of water vapor would begin to condense out of the air at atemperature of 28° C. (82° F.).

Diluting one part sample and two parts with air from the hospital roomwould reduce the water concentration in the tube down to 21.3 g/M³. Thisamount of water vapor would begin to condense out of the air at atemperature of 23.5° C. (74° F.).

An alternative approach would be to use bone dry air from the wall. Thiswill be available in the same box and could be piped to the samplelocation by means of a parallel tube.

The detectors are required to run at constant temperature so as toensure stability. Thus the inside of the detection module would be warm.A 50:50 dilution would work as long as the sample lines were insulatedby a thick wall or by having one tube run inside another.

Application (for 50% or 66% Dilution)

The sample tube could be spliced in two (or three), adjacent to thesampling point on the recuperator. Alternatively, the second samplingorifice could be molded into a special adaptor. It would be best not tohave a flapping air sample port, since it would raise too many questionsfrom users. This would allow for taking half the sample from the patientinspiratory line and half the sample from the room. Calibration wouldalso have to be at this point. Technically, this would be a perfectlyvalid way to operate and would meet all regulatory approval guidelines.Naturally, the approach be described in regulatory submissions whichwould also reference the EPA standard procedures.

Dilution at the sample point is a perfectly viable approach. There wouldalso probably be no need to have the large dead volume watercondensation trap on the detector. This would reduce the NO₂ formationlevel even further, by as much as a factor of 5. The life of detectorcells would increase from days to about 12 months, even during in housetesting. Dilution is the preferred method of sampling the reactive gasstream.

OTHER APPLICATIONS

The gas bottle alone can be used for all applications of NO. It isavailable to deliver the gas without any electronics whatsoever. Theadvantages of the system are simplicity, no mixing, no electronics andno software. Just connect the regulator and open the valve.

The gas bottle system can also be used with a dilutor. In this case thegas would be shipped as say 1000 ppm of NO₂ in oxygen. In a first stage,the user's equipment would then dilute this concentration down to say 20ppm NO₂. The second stage would be to insert the cartridge and convertto NO. this format would be similar to what is currently marketed, butwould not require the user to worry about any NO₂ that was formed in thegas lines since it would be removed by the recuperator. Similarly, therecuperator cartridge could be used with existing system to convert allof the residual NO₂ gas being inhaled into the therapeutic form, namelyNO. The recuperator also ensures that no NO gas is lost from the systemand that the patient is receiving the full prescribed dose.

The fact that the system can deliver high doses of NO, of the order of100 to 200 ppm or even higher, without the presence of the toxic form,NO₂, may be important. Much of the earlier work was done at doses in the20 ppm range, but the researchers were always plagued by the presence oftoxic NO₂. This limited the does that they could go to. With the systemall of the NO₂ toxicity problems in the inhaled gas are eliminated. Thisfact alone will greatly increase the utility of NO gas for treatment ofa multitude of diseases, and especially ARDS (Acute respiratory distresssyndrome).

Other implementations are within the scope of the following claims.

TABLE 1 Max Height Diameter Internal Weight Conc Name Inches InchesVolume L Pounds Pressure Volume L PPM LAB AS 48 8 29.45 48 2000 3600100(124) INCURRENT AQ/BL/88 33 7.25 15.57 30 2000 1918 200(233) USELUXFER ME36 25.3 4.4 4.5 8.3 3000 992 400(450)

TABLE 2 DISC RECUPERATOR PRESS DIAM D RADIUS r DROP mm THICKNESS INCHESINCHES r² AREA r⁴ cm H₂O H2O INCHES CM Base case 0.80 0.40 0.160 0.5030.0256 187.00 1870.00 5.5 13.97 1.00 0.50 0.250 0.785 0.0625 76.60765.95 3.52 8.94 1.50 0.75 0.563 1.767 0.3164 15.13 151.30 1.56 3.972.00 1.00 1.000 3.141 1.0000 4.79 47.87 0.88 2.24 2.50 1.25 1.563 4.9082.4414 1.96 19.61 0.56 1.43 3.00 1.50 2.250 7.068 5.0625 0.95 9.46 0.390.99 3.50 1.75 3.063 9.621 9.3789 0.51 5.10 0.29 0.73 4.00 2.00 4.00012.566 16.0000 0.30 2.99 0.22 0.56 4.50 2.25 5.063 15.903 25.6289 0.191.87 0.17 0.44 5.00 2.50 6.250 19.634 39.0625 0.12 1.23 0.14 0.36 constvolume

TABLE 3 DISC CYL CYL CYL DISC DISC PRESS CYL INSIDE OUTSIDE CYL CYLPRESS diam AREA DROP AREA rad rad LENGTH GAP DROP INCH sq inch cm-H20 sqin inch inch inch cm cm H2O 2.00 3.14 4.79 2.50 4.91 1.96 3.00 7.07 0.957.23 0.50 0.79 2.30 0.75 0.95 3.50 9.62 0.51 9.42 0.50 0.74 3.00 0.600.51 4.00 12.57 0.30 12.57 0.50 0.69 4.00 0.47 0.30 4.50 15.90 0.1915.58 0.62 0.78 4.00 0.40 0.19 5.00 19.63 0.12 19.70 0.57 0.70 5.50 0.320.12

1.-25. (canceled)
 26. A system of delivering a therapeutic amount ofnitric oxide to a mammal comprising: a ventilator, an NO₂ scavengerselected from the group consisting of proline, diphenylamine, asecondary amine and a tertiary amine, and a receptacle including aninlet, an outlet, and a surface-active material; wherein thesurface-active material includes an absorbent and a reducing agent; andwherein the inlet is configured to receive a gas flow and fluidlycommunicate the gas flow to the outlet through the surface-activematerial, such that nitrogen dioxide in the gas flow is converted tonitric oxide.
 27. The system of claim 26, wherein the absorbent issilica gel.
 28. The system of claim 26, wherein the absorbent isactivated alumina.
 29. The system of claim 26, further comprising a gassource of nitrogen dioxide, dinitrogen tetraoxide, or nitric oxide. 30.The system of claim 26, further comprising a gas source of nitric oxide.31. The system of claim 26, wherein the receptacle includes the NO₂scavenger.
 32. The system of claim 26, further comprising a humidifiedline.
 33. The system of claim 32, wherein the humidified line is heated.34. The system of claim 32, wherein the humidified line is heated toabout 35° C.